17alpha-(3-hydroxy-1-propynyl) or 17alpha-(3-hydroxy-1-propenyl) substituted aromatic steroids



United States Patent 1 18 Claims. ci. zen-397.5

This application is a continuation-in-part of the copending Christiansenapplication, Serial No. 328,212, filed December 5, 1963, now abandoned.

This invention relates to new aromatic steroid compounds, and inparticular is concerned with ring A-aromatic, 3,17B-dihydroxy steroidsbearing in the l7u-position a 3-hydroxy-1-propynyl or3-hydroxy-1-propenyl group; and with ethers and esters of said steroids.

A preferred aspect of the invention is concerned with compounds havingthe following general formula:

wherein Q is hydrogen or methyl; Q is hydrogen, methyl or lower-alkoxy;R and R are hydrogen, lower-alkyl, lower-alkenyl, cycloalkyl of 5-6 ringmembers, phenyl, phenyl-lower-alkyl, phenyl-lower-alkenyl,lower-carboxylic, acyl or nitro; R" is hydrogen, lower-alkyl, loweralkenyl, cycloalkyl of 56 ring members, phenyl-lower-alkyl,phenyl-lower-alkenyl, lower-carboxylic acyl, or nitro; and Y is C =-C orCH=CH; lower-carboxylic acyl in each instance having I to 12 carbonatoms and a molecular weight less than 250. Also included within thescope of the invention are compounds of the above formula having anadditional double bond in the 6,7-position, the 7,8-position or the9,11-position as well as compounds having two additional double bonds,in the 6,7- and the 8,9-positions.

The term lower-alkoxy used in defining Q in the above formula standsfor. an alkoxy groupof from 1 to 6 carbon atoms, thus including suchgroups as methoxy,

ethoxy, propoxy, isopropoxy, n-butoxy, n-hex'oxy, and the like.

The term lower-alkyl used in defining R,. R'and R" in the above formulastands for an alkyl group of from 1 to 10 carbon atoms, thus includingsuch groups as methyl, ethyl, propyl, isopropyl, butyl, pentyl,:hexyl,heptyl, octyl, nonyl, decyl, and the like.

The term lower-alkenyl" used in defining R, R and R in the above formulastands for an alkenyl group of from 3 to 10 carbon atoms, thus includingsuch groups as allyl, Z-butenyl, 3-butenyl, 3-pentenyl, 4-octeny-l,S-decenyl, and the like. v

The term cycloalkyl of 5-6 ring members used in defining R, R and R" inthe above formula stands for cyclopentyl, cyclohexyl or lower-alkylatedderivatives thereof, e.g., 3-methy1cyclopentyl, 4-ethylcyclohexyl, 3,4-dimethylcyclohexyl, and the like.

The terms phenyl-lower-alkyl and phenyl-loweralkenyl used in defining R,R and R" in the above 3,265,718 Patented August 9, 1966 formula standfor lower-alkyl and lower-alkenyl groups of the type describedhereinabove substituted by a phenyl group, thus including such groups asbenzyl, l-phenylethyl, 2+phenylethyl, 4-phenylbutyl, cinnamyl, 4-phenyl-2-butenyl, and the like. The phenyl group can, if desired be furthersubstituted by inert substituents sucjr as loweralkyl, lower-alkoxy andhalogen. r

When R, R or R stand for lower-carboxylic acyl groups, preferred classesof acylgroups include loweralkanoyl radicals, preferably having from 1to 12 carbon atoms, e.g., formyl, acetyl, propionyl, butyryl,isobutyryl, caproyl, heptanoyl octanoyl, dodecanoyl, trimethylacetyl,and the like; carboxy-lower-alkanoyl radicals, e.g., succinyl(fl-carboxypropionyl); cycloalkyl-lower-alkanoyl radicals, e.g.,B-cyclopentylpropionyl, fl-cyclohexylpropionyl, and the like; benzoyl;naphthalenecarbonyl; phenyl-loweralkanoyl or -alkenoyl radicals, such asphenylacetyl, B-phenylpropionyl, cinnamoyl, and the like;phenyloxylower-alkanoyl radicals, such as p-chlorophenoxyacetyl;pyridylcarbonyl, e.g., nicotinoyl and isonicotinoyl; carbanilyl; andthiocarbanilyl. In aryl radicals containing a phenyl group or a naphthylgroup, the aromatic ring can 7 Q. I R'O or the 6,7-dehydro, 7,8-dehydro,9,11-dehydro or 6,7;8,9- bis-dehydro analogs thereof, with an alkalimetal derivative of a compound of the formula HCECCH OR, whercin Q and Qhave the meanings given hereinabove, and R and R are hydrogen,lower-alkyl, lower-alkenyl, cycloalkyl of 5-6 ring members, phenyl,phenyl-lower-alkyl or phenyl-lower-alkenyl; and hydrolyzing the reactionmixture. The reaction of the l7-oxo steroid and alkali metal derivativetakes place at ordinary temperatures in an inert anhydrous solvent.

The foregoing process produces a compound of Formula I (or the dehydroanalogs thereof) wherein R and R are each either hydrogen, lower-alkyl,lower-alkenyl, cycloalkyl of 5-6 ring members, phenyl, phenyl-loweralkylor phenyl-lower-alkenyl; and R" is hydrogen. In the event that compoundswherein one or more of R, R and R" are lower-carboxylic acyl groups aredesired, they are produced from the corresponding free carbinols byesterification reactions, for example, by treating the carbinol with theappropriate acid anhydride or acid halide in the presence of pyridine.The primary hydroxy group (R=H) and the phenolic hydroxy group (R=H) arereadily esterified at room temperature. Esterification of the primaryhydroxy group (R=H) can also be carried out by heating the carbinol witha free acid, especially a lower-aliphatic carboxylic acid. In this waythe 3 primary hydroxy group (R=H) can be esterified without esterifyingthe phenolic hyd-roxy group (R'=H).

Esterification of the tertiary hydroxy group (R"=H) is effected onlyunder forcing conditions (extended heating). Accordingly, selectiveesterification of the primary hydroxy group (R"=H) can be performed.Conversely, the diesters (R and R"=acyl) can be selectively saponified,the primary acyloxy group being more readily hy' drolyzed, thus leadingto compounds where the tertiary hydroxy group "==H) only is esterified.

Nitrate esters (R and/or R'=NO,) are prepared by reacting the freecarbinols with a mixture of acetic anhydride and nitric acid.

Etherification of compounds of Formula I having free hydroxy groupswhere the entering R group is loweralkyl, lower-alkenyl, cycloalkyl of5-6 ring members, phenyl-lower-alkyl or phenyl-lower-alkenyl can beeffected by heating an alkali metal derivative of a free carbinol withan appropriate organic halide R-X, where X is chlorine, bromine oriodine.

The compounds of Formula I wherein Y is CH=CH are prepared by partialhydrogenation of the compounds of Formula I wherein Y is CEC. Thehydrogenation can be carried out catalytically, in which case thecisisomer is obtained. A preferred catalyst is palladium hydroxide onstrontium carbonate. The hydrogenation can also be carried out withlithium aluminum hydride, in which case the trans-isomer is obtained.

The structures of the compounds of the invention were established by themodes of preparation, by elementary analyses, and by their chemical andphysical properties, including their behavior in thin-layerchromatography.

Biological evaluation of the products of the invention has shown thatthey possess hypocholesteremic and estrogenie activity with the formeractivity predominating. The known hypocholesteremic agents possessconcomitant estrogenic activity which is usually unwanted because of thefeminizing side-effects produced. In the compounds of the presentinvention there is a marked separation in the hypocholesteremic andestrogenic activity, the latter being greatly reduced. Effective doselevels range from 1 to 50 mg./kg. and the compounds can be formulatedand administered to animal organisms in the same manner as othersteroidals hormones.

The following examples will further illustrate the invention without thelatter being limited thereby.

EXAMPLE 1 .3-methoxy-I 7a-(3-hydroxy-1-pr0pynyl) 1,3,5 1 -estratrien-1713-01 A mixture of 3.67 g. (0.160 mole) of lithium amide, 4.48 g.(0.080 mole) of propargyl alcohol and 200 ml. of dioxane was heated atreflux under nitrogen for two hours. There was then added 1 1.38 g.(0.040 mole) of estrone methyl ether, and the mixture was refluxed fortwo hours longer. The reaction mixture was cooled to room temperature,20 ml. of acetic acid added and the mixture allowed to stand overnight.The volatile solvent was then removed in vacuo on a steam bath, and theresidual material was partitioned between 300 ml. of methylenedichloride and 500 ml. of water. The organic layer was separated, driedover anhydrous sodium sulfate, filtered and concentrated to a volume of100 ml. The product which separated was recrystallized from amethanol-ethyl acetate mixture to give 3-methoxy-17a-(3-hydroxy-1-propynyl)-1,3,5(10)-estratrien-17fi-ol in the form ofcolorless plates, M.P. 174.0-175.4 C. (corn); [u] ='-5.9 (1% inchloroform).

3 methoxy 17a (3 hydroxy 1 propynyl) 1,3, 5(10)-estratrien-17fl-ol wasfound to possess hypocholesteremic activity (11 mg./kg./day, doserequired to reduce serum cholesterol by 33% in rats) and slightestrogenic activity (ED 1.70 mg./kg./day).

4 EXAMPLE 2 3-meth0xy-I 7a-(3-hydroxy-I -pr0pynyl) -1,3,5 (10)estratrien-I 7,8-0!

Potassium (83 g., 2.12 g. at.), cut into convenient sized lumps wasadded with stirring during approximately ten minutes to 1.0 liters ofliquid ammonia contained in a 5-liter, 3-necked flask equipped with astirrer and a condenser cooled with solid carbon dioxide. The mixturewas cooled in a solid carbon dioxide-isopropyl alcohol bath, andpropargyl alcohol (124 ml., 2.14 moles) was added dropwise with stirringover a period of one hour, followed by 300 g. (1.055 moles) of estronemethyl ether introduced portionwise over a period of ten minutes. Thecondenser and cooling bath were then removed and the reaction mixturestirred for two hours. After this period very gentle steam was appliedto the flask to hasten the evaporation of the ammonia and after one hourthe reaction temperature reached 0 C. The steam was turned off andstirring continued for an additional hour and one-half, during whichtime the temperature rose to 17 C. The reaction mixture was poured into6 liters of ice water with stirring, and concentrated hydrochloric acidwas slowly added until the suspension was just weakly basic. The mixturewas thendiluted with an additional 4 liters of cold water and stirringwas continued for an additional half hour. The resulting pale creamcolored product was collected by filtration, slurried once with waterand dried overnight. The dried product was stirred with 750 ml. ofmethylene dichloride at 0 C. for one-half hour, then collected andwashed with an additional 750 ml. of cold methylene dichloride, to give,after drying, 309 g. of3-rnethoxy-17u-(3-hydroxy-l-propynyl)-1,3-,5(10)-estratrien-l7;8-ol,M.P. 172-173 C. (uncorr.).

EXAMPLE 3 3 -meth0xy-1 7a-(3-acetoxy-1-pr0pynyl) -1,3,5 (10)estratrien-I 7,8-0l

A mixture of 3.00 g. of3-methoxy-17a-(3-hydroxy-lpropynyl)-1,3,5(10)-estratrien-17fi-ol(Example 1), 20 ml. of acetic anhydride and 20 ml. of pyridine wasstirred for seventeen hours at room temperature. The reaction mixturewas added to 400 ml. of ice water and the solid product was collected byfiltration, washed with water and dried. The product was recrystallizedfrom an acetone-cyclohexane mixture to give 2.82 g. of 3-methoxy-175u-(3-acetoxy-1-propynyl)-1,3,5(10)-estratrien-17fl-ol in the form ofcolorless prisms, M.P. 128.0-129.5 C.

(corn); [a] =8.l (1% in chloroform).

By replacing the acetic anhydride in the toregoing preparation by amolar equivalent amount of propionie anhydride, caproyl chloride,succinic anhydride, fi-cyclopentylpropionic anhydride, cinnamoylchloride, naphthale'ne-l-carboxylic acid chloride, nicotinoyl chloride,or pchlorophenoxyacetic anhydride there can be obtained, respectively,

3-methoxy-17a-( 3-propionoxy-1-propynyl -l ,3,5 10) estratrien-l 73-01,light beige prisms, M.P. 75 .2-76.8 C. (corn) (from acetone-cyclohexane)[a] ==-8.1 (1% in chloroform), 3-methoxy-17a-(3-caproyloxy-1-propynyl)-1,3,5 l0) estratrien-17fl-ol,3-methoxy-17a-[3-(fi-oarboxypropionoxy)-1-propynyl])-1,3,5(10)-estratrien-l7fi-ol, 3-methoxy-17a- 3-(B-cyclopentylpropionoxy)-1- propynyl] -1,3,5( 10) -estratrien-1 718-01,3-methoxy-17a-(3-cinna1moyloxy- 1 propynyl)- 1-propynyl]-l,3,510)-estratrien-17/3-ol, 1,3,5 10)-estratrien-l7fl-ol, 3-methoxy-17a- 3-naphthalenecarbonyloxy) 3-methoxy-17a-( 3-nicotinoyloxy-l -propynyl1,3,5( 10) -estratrien- 1718-01, or

. 3-methoxy-l7a- 3- rp-chlorophenoxyacetoxy) -1- propynyl] -1 ,3,5-estratrien-1 75-01.

By adding nitric acid to the reaction mixture of Example 3 above therecan be obtained 3-methoxy-17-(3- hydroxy-1-propynyl)--1,3,5(10)-estratrien-17p-ol 3-nitrate, colorless prisms, M.P.I07.0-107.8 C. (corr.), [u] =7.1 (1% in chloroform).

By adding formic acid to the reaction mixture of Example 3 above therecan be obtained 3-methoxy-17a- (3-formyloxy-1-propynyl) 1,3,5(10)-estratrien 17 8-01, colorless; prisms, M.P. 107.6-108.8 C. (corr.),

( 1% in chloroform).

By heating the reaction mixture in Example 3 above at reflux for abouteighteen hours there can be obtained3-methoxy-17fl-acetoxy-17a-(3-acetoxy-1-propyny1)-1,3,5-(10)-estratrien, as a yellow-brown glass, [a] =19.8 (1% in chloroform).

3-methoxy 17a-(3-hydroxy-1-propynyl) 1,3,5(10)- estratrien-17p-ol can becaused to react with phenyl isocyanate or phenyl isothiocyanate toafford, respectively,

3-methoxy-1-7a 3-carbanilyloxy-1-propyny1) 1,3,5 10) -estratrien- 17 -01or EXAMPLE 4 17a-(3-hydroxy-1-propynyl) 1,3,5 (10) -estratriene 3,17fi-diol was prepared from 5.41 g. of estrone, 3.13 of potassium and4.54 g. of propargyl alcohol inliquid ammonia according to the proceduredescribed above in Example 2. The crude product was acetylated with 32ml. of acetic anbydride in 32 ml. of pyridine, eighteen hours at roomtemperature, and the resulting 3-acetoxy- 17a-( 3-acetoxy-1-propynyl)1,3,5 10) -est ratrien-17fl-ol was dissolved in methylene dichloride andchromatographed on a column of 240 g. of alumina. The column was elutedsuccessively with pentane-ether, ether, and ether-methanol. The productbrought out by ethermethanol 95:5 was the deacetylated compound, 17a-(3-hydroxy-l-propynyl) 1,3,5(10)-estratriene 3,17,8-diol, colorless prisms,M.P. 218.0-220.0 C. (corr.);

(1% in chloroform). 1

17a 63 hydroxy ll propynyl) 1,3,5(10) estratriene-3,17/3-diol can becaused to react with propionic anhydride, caproyl chloride, succinicanhydride, fi-cyclopentylpropionic anhydride, be'nzoyl chloride,p-nitrobenzoyl chloride or cinnamoyl chloride, in the presence ofpyridine, to give, respectively,

1711 (3 hydroxy 1 propynyl) 1,3,4(10) estratriene-3,17B-diol when heatedat reflux with a mixture of acetic anhydride and pyridine for abouteighteen hours can be converted to3,17fi-diacetoxy-l7a-(3-acetoxy-lpropynyl)-1,3,5( 10) -estratriene.

6 EXAMPLE 5 3 heptyloxy 17oz (3 hydroxy 1 propynyl) 1,3,510)-estratrien-17B-ol was prepared from 7.37 g. of estrone, n-heptylether, 4.54 g. of propargyl alcohol and 3.13 g. of potassium in ml. ofliquid ammonia according to th procedure described above in Example2.The product was obtained in the form of colorless plates, M.P.139.6-l40.4 C. (corr.) when recrystallized from methylene dichloridecontaining about 5% acetonitrile; [oz] =-3.5 (1% in chloroform).

By replacing the estrone n-heptyl ether in the foregoing preparation bya molar equivalent amount of estrone ndecyl ether there can be obtained3-(n-decyl)oxy-l7a-(3- hydroxy-l-propynyl) 1,3,5( 10)-estratn'en-17p-ol.

EXAMPLE 6 3-cyclohexyloxy-l7a- (3-hydroxyl-propynyl) -1,3,5( 10)estratrien- 1 7,8-01 or3-(4metl1ylcyclohexyloxy)-17a-(3-hydroxy-1-pr0pynyl) 1,3 ,5 10-estratrien-17B-ol.

By replacing the estrone cyclopentyl ether in the foregoing preparationby a molar equivalent amount of estrone allyl ether, estrone benzylether or estrone cinnamyl ether, there can be obtained, respectively,

3-ally1oxy-17a-(3-hydroxy-1-propynyl)-1,3,5 10)-estratrien-l7fi-ol, tanplates, M.P. 137.0-139.9 C. (corr.3-benzyloxy-17a-(3-hydroxy-l-propynyl)-1,3,5(10)- estratrien-l7p-ol; orI 3-cinnamyloxy-17a-(3-hydroxy-1-pr0pynyl-1,3,5(10)- estratrien- 1 79-01.

EXAMPLE 7 3 methoxy 17a (3 methoxy 1 propynyl)1,3,5(10)-estratrien-l75-01 was prepared from 5.69 g. of

estrone methyl ether, 5.68 g. of methyl 2-propynyl ether and 3.13 g. ofpotassium in 100 ml. of liquid ammonia according to the proceduredescribed above in'Example 2. The crude product was dissolved in amethylene dichloride-pentane mixture and chromatographed on a column of200 g. of alumina. The column was eluted successiveq 1y with pentane,pentane-ether and ether, the last bringing out the desired product,3-methoxy-17a-(3-methoxy- 1-propynyl)-1,3,5(10)-estratrien-l7B-ol, M.P.89.0-91.2 C. (corr.) when recrystallized from cyclohexane; [u] =-7.4 (1%in chloroform).

By replacing the methyl 2-propynyl ether in the procedure of Example 7above by a molar equivalent amount of phenyl Z-propynyl ether, there canbe obtained 3- methoxy 17a (3 phenoxy 1 propynyl) 1,3,5(10)-estratrien-l7fl-ol, beige prisms, M.P. 103.0-107.0 C. (corr.), whenrecrystallized from acetonitrile;

( 1% in chloroform).

By replacing the methyl 2-propynyl ether in the foregoing preparation bya molar equivalent amount of n'decyl Lpropynyl ether, cyclopentylZ-propynyl ether or cyclohexyl 2-propynyl ether there can be obtained,respectively,

B-methoxy-171x-[3-(n-decyloxy)-1-propynyl] -1,3,5( 10)- estratrien-l75-01,

7 3-methoxy-17a- (3-cyclopentyloxy-l -propynyl) -l ,3 ,5 l)-estratrien-17fl-o1, or 3-methoxy-l 7a- 3-cyclohexyloxy-l-propynyl)-1,3,5 10) estratrien-17301.

By replacing the methyl Z-propynyl ether in the foregoing preparation bya molar equivalent amount of allyl Z-propynyl ether, benzyl Z-propynylether or cinnamyl Z-propynyl ether, there can be obtained,respectiv'ely, 3-methoxy-1 7a-( 3-allyloxy-l-propynyl) -l ,3,5( 10estratrien-17,301, 3-methoxy- 17a-( 3-benzyloxy-1-propynyl -1 ,3,5 10

estratrien-l7p-ol, or 3-methoxy-17a-( 3-einnamyloxyl-propynyl) -1,3,5 10

estratrien17fl-ol.

EXAMPLE 8 3 methoxy 17oz (3 hydroxy 1 propynyl) 1,3,5 (10),6estratetraen-17fi-ol was prepared from 5.65 -g. of 6-dehydroestronemethyl ether, 4.54 g. of propargyl alcohol and 3.13 g. of potassium in100 ml. of liquid ammonia according to the procedure described above inExample 2. The product was obtained in the form of colorless plates,M.P. 1682-1690 C. (corn), when recrystallized from ethyl acetate, [a]=-300.10 (1% in chloroform).

EXAMPLE 9 3 methoxy 17oz (3 hydroxy 1 propynyl)-1,3,5(10),6,8-estrapentaen-l7p-ol was prepared from 5.61 g. of equileninmethyl ether, 4.54 g. of propargyl alcohol and 3.13 g. of potassium in100 ml. of liquid ammonia according to the procedure described above inExample 2. The product was obtained in the form of beige prisms, M.P.l81.8183.4 C. (corn), when recrystallized from ethyl acetate; [oz]-=150.6 (1% in chloroform).

In a similar manner, l-methylestrone methyl ether or9(l1)-dehydroestrone methyl ether was reacted with propargyl alcohol andpotassium in liquid ammonia to give, respectively 3 methoxy 1 methyl17oz (3- hydroxy hydroxy 1 propynyl) 1,3,5(10) estratrien- 1% incloroform); and 3-methoxy-l7a-(3-hydroxy-1- propynyl) 1,3,5 (10),9( 11)estratetraen 17p ol, M.P. 167.0181.8 C. (corn), [oz] =+94.0 (1% inchloroform).

In a similar manner, Z-methoxyestrone methyl ether, Z-methylestronemethyl ether, or equilin methyl ether, can be reacted with propargy]alcohol and potassium in liquid ammonia to give, respectively,2,3-dimethoxy- 17oz (3 hydroxy 1 propynyl) 1,3,5(10) estratrien- 17fiol, 3 methoxy 2 methyl 17a (3 hydroxy-1-propynyl)-1,3,5(l0)-estratrien-l7fi-ol, or 3-methoxy- 17a (3 hydroxy 1propynyl) 1,3,5 (l0),7 estratetraen-17fi-ol.

EXAMPLE 10 3-methoxy-17a- [3- (3-phcnylpropionyloxy )-I-propynyl]1,3,5(10) -estratrien-1 75-01 3-phenylpropionyl chloride (137 g., 0.81mole) was added dropwise to a stirred solution of 250 g. (0.735 mole) of3 methoxy 170: a (3 hydroxy 1 propynyl)- 1,3,5 10)-estratrien-17fi-ol at-10 C. under anhydrous conditions. The reaction mixture was stirred at5-10 C. for one-half hour and then at room temperature for three hours.The reaction mixture was added to liters of water and the aqueousmixture extracted with 3 liters of ether. The ether extracts were washedwith dilute hydrochloric acid and aqueous sodium bicarbonate, and theaqueous washes were back-extracted with 3 liters of ether. The combinedether extracts were dried over anhydrous sodium sulfate and thenconcentrated in vacuo. The residue was dissolved in 1760 ml. of hotmethanol and the solution cooled to room temperature, filtered andseeded. Upon cooling to 0 C. there separated 261 g.

of 3 methoxy 17 [3 (3 phenylpropionyloxy)- 1 propynyl] 1,3,5( 10)estratrien 173 ol, M.P. 92.6- 95.4 C. (corn), [a] =-3.l (1% inchloroform).

By analogous procedures using the appropriate acid chloride were obained the followingesters:

3 methoxy 17a [3 benzoyloxy l propynyl)- 1,3,5(l0)-estratrien-l7fl-ol,colorless blades, M.P. l22.0 123.8 C. (mm) (from methylenedichloride-acetonitrile), [a] =-7.6 (1% in chloroform).

3 methoxy 17a [3 (p methoxybenzoyloxy)- 1 propynyl] 1,3,5(10) estratrien17,6 ol, M.P. 142.4-143.4 C. (corn) (from methylenedichlorideacetonitrile), [a] =-5.4 1% in chloroform).

3 methoxy 17a [3 (p chlorobenzoyloxy) 1- propynyl] 1,3,5 (10) estratrien175 ol, M.P. l14.6- ll6.0 C. (corn) (from methylenedichloride-acetonitrile), [a] ==3.2 (1% in chloroform).

3 methoxy 17a [3 (p methylbenzoyloxy) 1- propynyl] 1,3,5( 10 estratrien175 o1, colorless rods, M.P. 124.6-126.0 C. (corn) (from acetonitrile)(1% in cloroform).

3 methoxy 17a [3 (p fluorobenzoyloxy) 1- propynyl] 1,3,5(10) estratrien17,9 o1, colorless prisms, M.P. 128.6131.0 C. (corn) (fromacetonitrile), [a] =-6.1 (1% in chloroform).

3 methoxy 17a [3 (p nitrobenzoyloxy) 1- propynyl] 1,3,5 (10) estratrien17,9 ol, cream-colored powder, MLP. 138.5-1392" C. (corn) (frommethylene dichloride-acetonitrile), [a] =4.5 (1% in chloroform).

3 methoxy 17a [3 (3 pyridylcarbonyloxy)- 1 propynyl] 1,3,5(10)estratrien 17p ol, beige prisms, M.P. 160.016l.2 C. (corn) (frommethylene dichloride-acetonitrile), [u] =-8.6 (1% in chloroform). I

3 methoxy 17 (3 trimethylacetoxy 1 propynyl) 1,3,5 (10) estratrien 17pol, colorless rods, M,P. 112.2-113.6 C. (corn) (from methylenedichloride-acetonitrile), [a] =5.1 (1% in. chloroform).

3 methoxy 17a [3 (p dimethylaminobenzoyloxy) 1 propynyl] 1,3,5(10)estratrien 1713 ol, colorless prisms, M.P. 168.6-169.8 C. (corn) (fromethyl acetate), [a] =-7.8 (1% in chloroform).

3 methoxy 17a {3 [2 (p chlorophenoxy) 2- methyl propionoyloxy] 1propynyl} 1,3,5(10)- estratrien 17p 01, amorphous amberglass,

. ]D (1% in chloroform).

EXAMPLE 11 3,1 7 3-dimeth0xy-17a-(3-methoxy-I-propynyl)- 1,3,5 (1 0)-estratriene A mixture of 10.21 g. of 17a-(3-hydroxy-1-propynyl)-1,3,5(10)-estratriene-3,l7fl-diol, 4.10 g. of sodium hydride, 42.6 g. ofmethyl iodide and ml. of dimethylsulfoxide was stirred at roomtemperature for twentyseven hours. The material isolated from thereaction mixture was chromatographed on a column of silica gel andeluted with pentane-ether (83:15). The product was recrystallized from amethylene dichloridecyclohexane mixture to give 3,175 dimethoxy 17o: (3methoxy- 1-propynyl)-1,3,5(10)-estratriene, colorless needles, M.P.77.8-78.2 S. (oorr.), [a] =--13.4 (1% in chloroform).

EXAMPLE 12 17a- (3-acet0xy-1-propynyl) 1,3,5 (10) estratriene-3, 1 7fl-diol A mixture of 9.79 g. of 17a (3-hydroxy-1-propynyl)-1,3,5(10)-estratriene-3,17p-diol and 200 ml. of glacial diol, beigeprisms, M.P. l63.8l65.0 C. (corr.), [(11 =-8.l (1% in chloroform).

EXAMPLE l3 1 7,3-acetoxy-1 7a- (.i-hydroxy-I -propynyl) -3-methoxy-1,3,5'(10) -estratrl'em,

3 methoxy 173 acetoxy 17a (3 acetoxy 1- propynyl)-l,3,5(l)-estratriene(prepared by refluxing 6.81 g. of3-methoxy-l7e-(3-hydroxy-l-propynyl)-l,3,5 (l0)-estratriene-l7fi-ol withacetic anhydride in pyridine) was heated at reflux with a solution of 6g. of potassium bicarbonate in 180 ml. of methanol for a period of sevendays. The reaction mixture was poured into water and the solid productcollected by filtration and recrystallized from acetonitrile, usingactivated charcoal for decolorizing purposes, to givel7B-acetoxy-l7a-(3-hydroxy-l-propynl)-3-methoxy-l,3,5( l0)-estratriene,beige blades, M.P. ISIS-154.8 C. (corr.), [a] =-20.4 (1% in chloroform).

1 EXAMPLE 14 I a- (3-hydroxy-cis-I-propenyl) -3-methoxy- 1,3,5-estratrien-1 75-01 170: (3 hydroxy l propynyl) 3 methoxy 1,3,5l0)-estratrien-l7;3-ol (Example 1) (7.40 g.) and 0.50 g. of palladiumhydroxide on strontium carbonate catalyst was hydrogened in a Parrapparatus. After eight minutes the required amount of hydrogen had beentaken up, the mixture was filtered and the filtrate concentrated invacuo. The residue was crystallized from ethyl acetate to give 17w (3hydroxy cis l propenyl) 3.- methoxy -1,3,5(l0)- estratrien-17fl-ol,colorless needles, M.P. l43.8-145. 2 C. (corr.), [a] =+65.0 (1% inchloroform).

17a (3 hydroxy cis 1 propenyl) 3 methoxy- 1,3,5 (l0)-estratrien-l7fl-olwith acetic anhydride in pyridine at room temperature gavel7a-(3-acetoxy-ois-l-propcnyl) 3 methoxy l,3,5(10) estra trien 77/8 ol,M.P. l01.0-l03.0 C. (corn) when recrystallized from acetonitrile; [a]-==+70.0 (1% in chloroform).

EXAMPLE 1711- (3-hydroxy-trans-1propenyl) -3-methoxy- 1,3,5 (10)-e.rtratrien-1 75-01 Lithium aluminum hydride (0.78 g.) was added to asolution of 3.40 g. of 17a-(3-hydroxy-1-propynyl)-3- methoxy-l,3,5(l0)-estratrien-17fl ol (Example 1), and the mixture'was heated at refluxunder nitrogen for two and one-half hours. The reaction mixture wasallowed to stand at room temperature overnight, 1.6 ml. of water wasadded dropwise with stirring, and after five hours the mixture wasfiltered and the filtrate concentrated in vacuo. The residue wasrecrystallized twice from a tetrahydrofuran-ethyl acetate mixture togive l7a-(3-hydroxy-transl-propenyl) -3-methoxy-l,3,5(10)-es,tratrien-l7fl-ol, colorless needles, M.P. l-80.0-l81.0 C.(corr).; b11 +38.2 (1% in chloroform).

17a (3 hydroxy trans 1 propenyl) 3 methoxy- 1,3,5(l0)-estratrien-l7fl-ol with acetic anhydride in pyridine at roomtemperature gave17a-(3-acetoxy-cis-l-propenyl)-3-methoxy-l,3,5(l0)-est7ratrien-l748-01,M.P. 85.0 87.0- C. -(corr.) when recrystallized from acetonitrile; [a]-=+35.7 (1% in chloroform).

10 I claim: 1. (A) A compound of the formula y-cm-ou wherein Q ishydrogen or methyl; Q is hydrogen, methyl or l-ower-alkoxy; R and R arehydrogen, lower-alkyl, lower-alkenyl, cycloalkyl of 5-6 ring members,phenyl, phenyl-lower-alkyl, phenyl-lower-alkenyl, lower-carboxylic acyl,or nitro; R is hydrogen, lower-alkyl, lower-alkenyl, cycloalkyl of 5-6ring members, phenyl-lower-alkyl, phen yI-lower-alkenyl,lower-carboxylic acyl, or nitro; and Y is CEO or CH=CH; lower-carboxylicacyl in each in stance having 1 to 12 carbon atoms and a molecularweight less than 250; (B) a compound of the above formula having adouble bond in the 6,7- 7,8- or 9,1 l-position; or (C) a compound of theabove formula having a double bond in the 6,7-position and a double bondin the 8,9-position.

2. A compound of the formula caoomon ozocmon wherein R is lower-alkyl.

4. A compound of the formula on=cHorr=on wherein R is lower-carboxylicacyl having from 1 to 12 carbon atoms and a molecular weight less than250, and R is lower-alkyl.

1. (A) A COMPOUND OF THE FORMULA